In this project, we propose to develop controlled release inhalable formulations of drugs used for the treatment of pulmonary arterial hypertension (PAH), a rare but debilitating and lethal disorder that affects around 50,000 to 100,000 people in the United States. Current therapy for PAH is challenging with regard to ease of administration, safety, efficacy and stability. Medications currently used to treat PAH include endothelial receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclin analogues. Of these, prostacyclin analoguesgepoprostenol, treprostinil, and iloprostgare considered the first-line therapeutic agents. However, a major shortcoming of this class of drugs is their very short half-lives, which requires that they be administered by continuous infusion or multiple dosings per day. The risks associated with the use of a central catheter, infection at the site of administration, instability of the formulations at room temperature, and cardiovascular collapse due to interruption of infusion are the potentially serious complications of PAH therapy with epoprostenol and treprostinil. Although an inhaled prostacyclin analogue, iloprost, is currently available, this drug must be inhaled 9-12 times per day because of its short half-life of 20-30 minutes. Recently, fasudilgan investigational drug that belongs to a new class of anti-PAH drugsghas shown potential in reducing PAH in animal models. However, there is currently no data on the long-term safety and efficacy of the drug for the treatment of PAH. The challenges associated with current PAH therapy can be overcome by formulating them in inhalable controlled release polymeric and lipidic nano- or microparticles for selective and long-term pulmonary arterial activity. Thus, the hypothesis to be tested in this project is: Anti-PAH drugs encapsulated in long-acting inhalable particles are an efficacious and patient-compliant therapy for the long-term treatment of PAH. The objectives of this study will be accomplished by formulating iloprost, a commercially available inhalable prostacyclin analogue, and fasudil, a Rho-kinase inhibitor, in controlled release particulate carriers. The proposed formulations will initially be tested in vitro and in vivo for their suitability to be delivered via the pulmonary route. The efficacies of the formulations of the two drugs will be tested and cross-compared in PAH-induced rodent models. The safety will be investigated in three sets of experiments bronchoalveolar lavage, measurement of mucociliary transport rate, and assessment of the histopathological changes in the lungs. The long-term goal of this project is to generate preclinical data on the safety and efficacy of the proposed delivery system, so that further testing can be carried out in healthy volunteers and patients with PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a rare disease that restricts the flow of blood through the pulmonary arteries of the lungs, which leads to right heart failure and death. Epoprostenol, treprostinil, and iloprost are three important drugs that are currently used to treat PAH. Unfortunately, the first two drugs must be administered by using an intravenous catheter and the third one must be inhaled 6 to 12 times a day. These problems limit the effectiveness of these drugs in the treatment of PAH. In this project, we propose to develop a controlled release inhalable formulation of iloprost and an investigational drug fasudil and compare the efficacy of one drug with the other. If successful, identification of a long-lasting and efficacious inhalable formulation will eliminate the need for a catheter and multiple daily dosings. This will improve the quality of life and survival of patients with this devastating disease.